Stress is accompanied by the activation of a number of endocrine secretions. Of these, adrenal glucocorticoids play a pivotal role as the principal regulators of the brain-pituitary response to stress and as agents which restore homeostatic balance and also protect the body from its own defense mechanisms such as inflammation and immune reactions. Though the body cannot long endure the absence of stress hormones, prolonged elevation of these hormones can have deleterious, even disastrous, effects such as increased susceptibility to infections and cancer. In addition the brain may also suffer in ways which are long-lasting and even permanent through glucocorticoid-induced neuronal loss and other long-term compensatory changes in neurochemical function which may influence mood and cognitive performance as well as the stress-response mechanism. This proposal investigates how prolonged stress and persistent and repeated elevation of glucocorticoid hormones alter neurochemistry of the principal adrenal steroid target area of the brain, the hippocampus, as well as of hormone sensitive areas of the limbic system and the frontal cortex. Having established glucocorticoid effects on glucocorticoid receptor levels, neurotransmitter receptor binding, cAMP formation stimulated by neurotransmitters, Synapsin I levels and mRNA and VIP levels and mRNA, we intend to investigate the degree to which effects of persistent and repeated glucocorticoid elevation (eg., 6-12 weeks duration) may be irreversible and reflect either the loss of cells or the compensatory response of the brain to cell loss. Finally, we shall determine whether the effects of repeated glucocorticoid elevation are cumulative or can be alleviated by periodic interruptions of stress hormone exposure. This work has relevance to degenerative brain diseases such as Alzheimer's endogenous depressive illness, and the study of persistent or chronic stress in loneliness, grieving, or isolation from normal life situations (eg., hostages, prisoners of war).